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Human Renal Cancer Cells Express a Novel Membrane-Bound Interleukin-15 that Induces, in Response to the Soluble Interleukin-15 Receptor Chain, Epithelial-to-Mesenchymal Transition

¹ Institut National de la Sante et de la Recherche Medicale UMR 542, Université de Paris-Sud, Hôpital Paul Brousse; ² Institut National de la Sante et de la Recherche Medicale UMR 753, Université de Paris-Sud, Institut Gustave Roussy, Villejuif, France; ³ Institut National de la Sante et de la Recherche Medicale U 567, Institut Cochin, Paris, France; ⁴ Laboratory of Immunotherapy, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; and ⁵ Institute for Pharmacology, RWTH Aachen University, Aachen, Germany

Requests for reprints: Azzarone Bruno, Institut National de la Sante et de la Recherche Medicale, UMR 542, Bâtiment Lavoisier, Hôpital Paul Brousse, 14, Avenue Paul Vaillant Couturier, 94807, Villejuif Cedex, France. Phone: 33-0145595343; Fax: 33-0145595344; E-mail: bazzarone{at}hotmail.com.

Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor (s-IL-15R) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to ~induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15R subunit that tunes its signaling potential competing with low concentrations of the s-IL-15R chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression. [Cancer Res 2009;69(4):1561–9]